CC chemokine ligand 2 (CCL2) promotes prostate cancer tumorigenesis and metastasis

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Abstract

CCL2 is a chemokine known to recruit monocytes and macrophages to sites of inflammation. A growing body of research suggests CCL2 is progressively overexpressed in tumor beds and may play a role in the clinical progression of solid tumors. Cancer cells derived from several solid tumor types demonstrate functional receptors for CCL2, suggesting this chemokine may achieve tumorigenicity through direct effects on malignant cells; however, a variety of normal host cells that co-exist with cancer in the tumor microenvironment also respond to CCL2. These cells include macrophages, osteoclasts, endothelial cells, T-lymphocytes, and myeloid-derived immune suppressor cells (MDSCs). CCL2 mediated interactions between normal and malignant cells in the tumor microenvironment and plays a multi-faceted role in tumor progression.

Introduction

Cancer cells co-exist in the tumor microenvironment with normal host cells, including hematopoietic precursors. While some host cells inhibit cancer growth, many produce a multitude of soluble factors and nutrients that promote tumor progression and growth. In turn, cancer cells provide growth factors, cytokines, and chemokines that promote host cell proliferation and survival. Understanding the factors that contribute to this vicious cycle of cooperation is of primary importance to understanding malignant progression and has revealed new therapeutic targets for cancer treatment.

Altered regulation of chemokines and their receptors has been demonstrated to promote tumor development and progression through multiple mechanisms including enhanced proliferation, increased invasiveness, increased angiogenesis, and recruitment of immune cells [as reviewed in [1], [2], [3]]. Among the many chemokines and their receptor pairs, CC chemokine ligand 2 (CCL2) and its receptor CCR2 have recently been shown to play key roles in promoting tumorigenesis and metastasis [as reviewed in [4]].

CCL2 is a member of the CC chemokine family that regulates the recruitment of monocytes, macrophages, and other inflammatory cells to sites of inflammation via activation of CCR2 [5]. In addition to its role in inflammatory responses, CCL2 has been demonstrated to directly stimulate prostate cancer cell chemoattraction, proliferation, and survival [6], [7], [8]. CCL2 has also been shown to play a central role in the maturation of osteoclasts in the microenvironment of skeletal metastases [9]. The multiple roles of CCL2 in the promotion of tumorigenesis make the CCL2/CCR2 axis an attractive therapeutic target for cancer treatment (Fig. 1 and Table 1).

Section snippets

CCL2 and its receptor CCR2

CCL2, also known as monocyte chemoattractant protein-1 (MCP-1), was first identified by its ability to attract monocytes in vitro [10], [11], [12]. CCL2 is a 76-amino acid polypeptide and is a member of the C–C chemokine family characterized by adjacent cysteine residues. It binds with high affinity to the seven transmembrane G-protein coupled receptor CCR2. The CCL2 gene is one of several cytokine genes clustered on the q-arm of chromosome 17 [13].

Investigations of CCL2 and CCR2 genotypic

CCL2 is present in the tumor microenvironment

CCL2 expression has been demonstrated in many cancer types including prostate, breast, lung, melanoma, ovary, gastric, renal, colorectal, esophageal and multiple myeloma [as reviewed in [4]]. Prostate cancer in particular demonstrated elevated CCL2 expression in malignancies when compared to benign prostatic tissues [8]. One study identified 4-fold up-regulation of CCL2 as determined by cytokine antibody arrays comparing the tumor-bone microenvironment to non-neoplastic bone [6]. CCL2 is

CCL2 and prostate cancer cell proliferation and survival

Recombinant human CCL2 induces dose-dependent prostate cancer cell proliferation in vitro through the activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway [6], [8]. In addition, this activation of the AKT pathway also provides cancer cells with a survival advantage through up-regulation of survivin [26]. Specifically, PI3K/Akt activation by CCL2 mediates mTORC1 activation, survivin up-regulation, and subsequent down-regulation of autophagosome formation. Autophagy protects cells

CCL2 and tumor angiogenesis

Angiogenesis correlates with cancer progression and/or poor prognosis in a variety of solid tumors [29]. The process can be activated at different stages of tumor development, depending on the cancer types and the tumor microenvironment. Identifying critical angiogenic factors and mediators in the tumor microenvironment remains an important challenge.

Previous findings suggest that CCL2 can directly mediate angiogenesis in endothelial cells, which express CCR2 [30]. Human brain endothelial

CCL2 and TAMs in the tumor progression

Many solid tumors contain an inflammatory infiltrate that often comprises a majority of the cells in the tumor's mass [39]. In many tumors, the majority of the infiltrating cells are TAMs derived from myeloid progenitor cells in the bone marrow compartment [40]. Myeloid progenitor cells develop into pro-monocytes in the bone marrow prior to being released into the circulation where they undergo differentiation into monocytes. Monocytes then migrate into tissues where they differentiate into

The effect of CCL2 on osteoclasts

Prostate cancer preferentially metastasizes to bone, resulting in high mortality. Histopathological examination of tumor-induced bone lesions reveals a mixture of pre-requisite osteolytic bone resorption and a predominantly bone forming osteoblastic reaction. The tumor-induced osteoclast activity is essential for prostate cancer establishment in the bone microenvironment.

It has been reported that blocking Receptor Activator of Nuclear Factor KappaB Ligand (RANKL) in murine models partially

The effects of CCL2 on T-lymphocytes in the tumor microenvironment

Several studies have demonstrated CCL2 overexpression at sites of inflammation and the contribution of CCL2 to the inflammatory components of such diseases as atherosclerosis, multiple sclerosis, and rheumatoid arthritis [5], [48]. In addition, growing evidence has implicated chemokines as a key component of cancer-related inflammation due to the role of chemokines in inflammatory cell recruitment and function in the tumor microenvironment [36]. Although, CCL2 is chemoattractant not only for

The effects of CCL2 on immune suppressor cells

Failure of host anti-tumor immunity may be caused by exaggerated suppression of tumor-associated antigen-reactive lymphocytes. Suppression of reactive lymphocytes is mediated by regulatory T-cells (Tregs). Tumor-derived TGFβ can convert CD4+ CD25 T cells into CD4+ CD25+ T cells, which is one immune evasion mechanism available to tumor cells [55]. Other mechanisms include production of the immunosuppressive cytokine IL-10 [56], generation of immunosuppressive DCs [57], and induction of T-cell

Conclusion

CCL2 influences cancer tumorigenesis and metastasis via distinct mechanisms:

  • (1)

    A direct promotional effect on tumor cell growth, survival and function

  • (2)

    A modulatory effect on the tumor microenvironment by promoting macrophage mobilization and infiltration into the tumor bed

  • (3)

    Promotion of osteoclast maturation in the bone tumor microenvironment

  • (4)

    Suppression of cytotoxic lymphocytes.

Direct CCL2 stimulation regulates the growth, survival, invasiveness, and migration of tumor cells. This ability to

Acknowledgements

This work was supported by the DOD PC061231 (JZ); NIH PO1 CA093900 (KJP), an American Cancer Society Clinical Research Professorship (KJP), NIH SPORE P50 CA69568 (KJP), Cancer Center P30 CA46592 (KJP), Southwest Oncology Group CA32102 (KJP), and Prostate Cancer Foundation (KJP)

Jian Zhang received his M.D. degree in internal medicine from Tianjin Medical University, Tianjin, China, in 1986, a M.S. in immunology from the Old Dominion University and Eastern Virginia Medical School, Norfolk, Virginia, in 1998, and a Ph.D. in pathology from the University of Michigan, Ann Arbor, Michigan, in 2001. After a three-year postdoctoral fellowship at the University of Michigan, he was promoted to an assistant professor at the University of Pittsburgh, Pittsburgh, Pennsylvania. He

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    Jian Zhang received his M.D. degree in internal medicine from Tianjin Medical University, Tianjin, China, in 1986, a M.S. in immunology from the Old Dominion University and Eastern Virginia Medical School, Norfolk, Virginia, in 1998, and a Ph.D. in pathology from the University of Michigan, Ann Arbor, Michigan, in 2001. After a three-year postdoctoral fellowship at the University of Michigan, he was promoted to an assistant professor at the University of Pittsburgh, Pittsburgh, Pennsylvania. He recently joined the University of Michigan, Department of Internal Medicine and Michigan Center for Translational Pathology and the University of Michigan Comprehensive Cancer Center. His research interests have been focused on the study of bidirectional and dynamic interaction between cancer cells and the cells in the tumor microenvironment. In particular, he has expertise in biomarker discovery and preclinical animal models in cancer and its metastasis. He is the author/coauthor of over 50 scientific publications and a reviewer for DOD panel of cancer pathobiology and Cancer research UK program.

    Lalit Patel is a research laboratory technician at the University of Michigan Cancer Center and a graduate student in the Department of Biomedical Engineering. He holds a bachelor of science in biomedical engineering from the Fu Foundation School of Engineering and Applied Science at Columbia University. Prior to joining the University of Michigan, Lalit held an appointment at the Prostate Cancer Foundation.

    Dr. Kenneth J. Pienta is a professor of internal medicine and urology, a two-time American Cancer Society Clinical Research Professor Award recipient, and Director of Experimental Therapeutics for the Michigan Center for Translational Pathology. Dr. Pienta is the Associate Dean for Clinical and Translational Research at the University of Michigan Medical School and Director of the Michigan Institute for Clinical and Health Research. Since 1995, Dr. Pienta has been the Director of the Prostate Specialized Program of Research Excellence (SPORE) at The University of Michigan. He has a proven, peer-reviewed track record in organizing and administering a translational research program that successfully incorporates bench research, agent development, and clinical application. Dr. Pienta has international expertise in the development of novel chemotherapeutic programs for prostate cancer. Currently, Dr. Pienta is involved in research to define the tumor microenvironment of prostate cancer metastases, as well as developing new therapies for prostate cancer.

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